Platelet-derived growth factor receptor

Platelet-derived growth factor receptor
File:PDGF receptor.png Crystal structure of the PDGF receptor
Identifiers
Symbol	?
PDB	3MJG
Other data
EC number	2.7.10.1
Locus	Chr. 4 q12-q13.1

The Platelet-derived growth factor receptor (PDGFR) is a cell surface receptor that plays a crucial role in cell growth, development, and wound healing. It is a member of the receptor tyrosine kinase (RTK) family and is activated by binding to its ligands, the platelet-derived growth factors (PDGFs). The PDGFR is encoded by the PDGFR gene located on chromosome 4q12-q13.1.

Structure

The PDGFR protein consists of an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain contains five immunoglobulin-like domains, which are responsible for ligand binding. The transmembrane domain anchors the receptor to the cell membrane, while the intracellular domain contains the tyrosine kinase activity.

The crystal structure of the PDGFR has been determined, revealing the arrangement of its domains and the mechanism of ligand binding. The receptor forms a dimer upon ligand binding, leading to the activation of its tyrosine kinase activity.

Function

The PDGFR plays a crucial role in various cellular processes, including cell proliferation, migration, and differentiation. Upon ligand binding, the receptor undergoes autophosphorylation, leading to the recruitment and activation of downstream signaling molecules. These signaling pathways regulate gene expression and control cellular responses.

The PDGFR is expressed in various cell types, including fibroblasts, smooth muscle cells, and certain types of cancer cells. It is involved in tissue repair and regeneration, as well as in the development of certain diseases, such as cancer and fibrosis.

Ligands

The PDGFR binds to its ligands, the PDGFs, which are dimeric proteins consisting of two A or two B chains. The PDGFs are secreted by various cell types, including platelets, macrophages, and endothelial cells. They bind to the extracellular domain of the PDGFR, leading to receptor dimerization and activation.

There are four known PDGF isoforms: PDGF-AA, PDGF-BB, PDGF-AB, and PDGF-CC. Each isoform has a specific affinity for the PDGFR and can activate different downstream signaling pathways.

Signaling pathways

Upon activation, the PDGFR initiates several signaling pathways, including the Ras-MAPK pathway, the PI3K-Akt pathway, and the PLCγ pathway. These pathways regulate cell proliferation, survival, and migration.

The Ras-MAPK pathway is involved in cell proliferation and differentiation. It activates the mitogen-activated protein kinase (MAPK) cascade, leading to the phosphorylation of various transcription factors and the induction of gene expression.

The PI3K-Akt pathway regulates cell survival and growth. It activates the protein kinase Akt, which phosphorylates and regulates various downstream targets involved in cell survival and metabolism.

The PLCγ pathway is involved in cell migration and cytoskeletal rearrangement. It activates phospholipase Cγ (PLCγ), leading to the production of inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers the release of calcium ions from the endoplasmic reticulum, while DAG activates protein kinase C (PKC), which regulates cytoskeletal dynamics.

Clinical significance

Aberrant activation of the PDGFR signaling pathway has been implicated in various diseases, including cancer and fibrosis. Mutations in the PDGFR gene can lead to constitutive activation of the receptor, resulting in uncontrolled cell growth and tumor formation.

Several drugs targeting the PDGFR have been developed for the treatment of cancer and fibrosis. These drugs, known as PDGFR inhibitors, block the tyrosine kinase activity of the receptor, thereby inhibiting downstream signaling pathways and reducing cell proliferation.